The relative predictive value of undergraduate versus graduate selection tools in two Australian medical schools.

Context: Monash University and the University of Western Australia admit both school-leavers and graduates into their Bachelor of Medicine and Bachelor of Surgery (MBBS) courses. The Undergraduate Medicine and Health Sciences Admission Test (UMAT) and the Graduate Medical Schools Admissions Test (GAMSAT) are used for selection, along with an academic score and an interview score. The aim of this study was to compare the relative predictive validity of the selected components in the two entry streams, particularly UMAT versus GAMSAT. Methods: Aggregated scores for course outcomes were calculated in the categories of knowledge, clinical and total scores, at four-time points. A path analysis was conducted based on multivariate regressions with model constraint parameters defined across the outcome variables to investigate change over time. Results: Academic scores were the strongest predictors of knowledge scores and end of course results. Interview scores had a small positive increasing effect, being stronger for clinical than knowledge outcomes. The effect size for GAMSAT was greater than for UMAT. Conclusions: Aptitude tests and interview scores added small but significant incremental predictive value to previous academic achievement. GAMSAT showed larger predictive value on outcomes than UMAT, for which one section (UMAT 3) had a negative effect.

A Randomized Trial of Effects of Alcohol on Cytochrome P450 Eicosanoids, Mediators of Inflammation Resolution, and Blood Pressure in Men.

BACKGROUND: Cardiovascular effects of alcohol consumption may be influenced by both pro- and anti-inflammatory mechanisms. We previously showed that chronic alcohol consumption increased blood pressure (BP), oxidative stress, and 20-hydroxyeicosatetraenoic acid (20-HETE), a vasoconstrictor and pro-inflammatory eicosanoid synthesized by cytochrome P450 (CYP450) enzymes from arachidonic acid. This study in men examined the effect of consuming red wine (RW) on BP in relation to changes in 20-HETE, oxidative stress (F2 -isoprostanes), markers of inflammation, anti-inflammatory CYP450 epoxyeicosatrienoic acids (EETs), and specialized pro-resolving mediators of inflammation (SPMs) derived from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). METHODS: Normotensive men (n = 22) were randomly allocated to drink RW (375 ml/d) or the equivalent volume of dealcoholized red wine (DRW) or water for 4 weeks in a 12-week, 3-period crossover trial. BP, heart rate, 20-HETE, F2 -isoprostanes, and SPM were measured at baseline, 4, 8, and 12 weeks. RESULTS: Drinking RW increased BP (p < 0.05), plasma and urinary 20-HETE (p < 0.05), plasma F2 -isoprostanes (p < 0.0001), and the SPMs 18-hydroxyeicosapentaenoic acid (18-HEPE) from EPA, and resolvin D1 (RvD1) and 17R-resolvin D1 (17R-RvD1) from DHA (all p < 0.05) compared with DRW and water. EETs and high-sensitivity C-reactive protein were unaffected by RW. Plasma 18-HEPE was positively related to urinary 20-HETE (p < 0.008) only after RW. CONCLUSIONS: This study has shown that men consuming moderate-to-high alcohol as RW for 4 weeks had increased BP, 20-HETE, and oxidative stress, as well as specific SPM that resolve inflammation. These paradoxical findings require further studies to determine whether alcohol stimulates different CYP450 enzymes and whether the findings can be replicated in females.

Acute effects of chlorogenic acids on endothelial function and blood pressure in healthy men and women.

Coffee is a rich source of polyphenols, primarily chlorogenic acids (CGA). Certain polyphenols and polyphenol-rich foods and beverages have been shown to improve endothelial function and lower blood pressure (BP). The aim of the present study was to investigate the acute effect of two doses of CGA (5-CGA) on endothelial function and BP. In a cross-over study, 16 healthy men and women received: (i) 0 mg purified 5-CGA (control group); (ii) 450 mg purified 5-CGA; (iii) 900 mg purified 5-CGA; and (iv) 200 mg purified (-)-epicatechin (positive control) in random order one week apart. Peak and continuous mean (60 to 240 s post ischaemia) flow-mediated dilation (FMD) was measured at baseline, 1 h and 4 h. BP was measured at baseline and every 30 min to 4 h. Plasma CGA and epicatechin levels were significantly increased at both 1 h and 4 h post their respective treatments. Peak FMD was not significantly altered by either dose of 5-CGA or the epicatechin, relative to control (p > 0.05). Relative to control, effects on continuous mean FMD response following 450 mg 5-CGA and 900 mg of 5-CGA (0.47 ± 0.16%, p = 0.016 and 0.65 ± 0.16%, p < 0.001, respectively) at 1 h and (0.18 ± 0.17%, p = 0.99 and 0.44 ± 0.16%, p < 0.05, respectively) at 4 h. There was no significant effect of any of the treatments on BP. In conclusion, the present study has found no significant effect of 5-CGA, at 450 and 900 mg, on peak FMD response. However, there were significant improvements in mean post-ischaemic FMD response, particularly at the 1 h time point in this group of healthy individuals.

Effects of vitamin E, vitamin C and polyphenols on the rate of blood pressure variation: results of two randomised controlled trials.

High blood pressure (BP) variability, which may be an important determinant of hypertensive end-organ damage, is emerging as an important predictor of cardiovascular health. Dietary antioxidants can influence BP, but their effects on variability are yet to be investigated. The aim of the present study was to assess the effects of vitamin E, vitamin C and polyphenols on the rate of daytime and night-time ambulatory BP variation. To assess these effects, two randomised, double-blind, placebo-controlled trials were performed. In the first trial (vitamin E), fifty-eight individuals with type 2 diabetes were given 500 mg/d of RRR-α-tocopherol, 500 mg/d of mixed tocopherols or placebo for 6 weeks. In the second trial (vitamin C-polyphenols), sixty-nine treated hypertensive individuals were given 500 mg/d of vitamin C, 1000 mg/d of grape-seed polyphenols, both vitamin C and polyphenols, or neither (placebo) for 6 weeks. At baseline and at the end of the 6-week intervention, 24 h ambulatory BP and rate of measurement-to-measurement BP variation were assessed. Compared with placebo, treatment with α-tocopherol, mixed tocopherols, vitamin C and polyphenols did not significantly alter the rate of daytime or night-time systolic BP, diastolic BP or pulse pressure variation (P>0·05). Treatment with the vitamin C and polyphenol combination resulted in higher BP variation: the rate of night-time systolic BP variation (P= 0·022) and pulse pressure variation (P= 0·0036) were higher and the rate of daytime systolic BP variation was higher (P= 0·056). Vitamin E, vitamin C or grape-seed polyphenols did not significantly alter the rate of BP variation. However, the increase in the rate of BP variation suggests that the combination of high doses of vitamin C and polyphenols could be detrimental to treated hypertensive individuals.

Dietary quercetin attenuates oxidant-induced endothelial dysfunction and atherosclerosis in apolipoprotein E knockout mice fed a high-fat diet: a critical role for heme oxygenase-1.

Several lines of evidence indicate that quercetin, a polyphenol derived in the diet from fruit and vegetables, contributes to cardiovascular health. We aimed to investigate the effects of dietary quercetin on endothelial function and atherosclerosis in mice fed a high-fat diet. Wild-type C57BL/6 (WT) and apolipoprotein E gene knockout (ApoE(-/-)) mice were fed: (i) a high-fat diet (HFD) or (ii) a HFD supplemented with 0.05% w/w quercetin (HFD+Q), for 14 weeks. Compared with animals fed HFD, HFD+Q attenuated atherosclerosis in ApoE(-/-) mice. Treatment with the HFD+Q significantly improved endothelium-dependent relaxation of aortic rings isolated from WT but not ApoE(-/-) mice and attenuated hypochlorous acid-induced endothelial dysfunction in aortic rings of both WT and ApoE(-/-) mice. Mechanistic studies revealed that HFD+Q significantly improved plasma F2-isoprostanes, 24h urinary nitrite, and endothelial nitric oxide synthase activity, and increased heme oxygenase-1 (HO-1) protein expression in the aortas of both WT and ApoE(-/-) mice (P<0.05). HFD+Q also resulted in small changes in plasma cholesterol (P<0.05 in WT) and plasma triacylglycerols (P<0.05 in ApoE (-/-)mice). In a separate experiment, quercetin did not protect against hypochlorite-induced endothelial dysfunction in arteries obtained from heterozygous HO-1 gene knockout mice with low expression of HO-1 protein. Quercetin protects mice fed a HFD against oxidant-induced endothelial dysfunction and ApoE(-/-) mice against atherosclerosis. These effects are associated with improvements in nitric oxide bioavailability and are critically related to arterial induction of HO-1.

Short-term effects of polyphenol-rich black tea on blood pressure in men and women.

There is increasing evidence that black tea polyphenols contribute to vascular health. We have recently shown that regular ingestion of polyphenol-rich black tea over 6 months results in lower systolic and diastolic blood pressure. However, the time course of these effects remains unclear. Therefore, our objective was to determine if short-term effects of tea on blood pressure could contribute to longer-term benefits of regular tea consumption on blood pressure. Men and women (n = 111) were recruited to a randomised placebo-controlled double-blind parallel designed trial. During a 4-week run-in, all participants consumed 3 cups per day of black tea. Participants then consumed 3 cups over 1 day of either powdered black tea solids containing 429 mg of polyphenols (tea), or a control product matched in flavour and caffeine content but containing no tea solids. The 24 h ambulatory blood pressure and heart rate was measured at the end of the 4-week run-in (baseline) and again during the 24 h intervention period. The 24 h day-time and night-time blood pressures were not significantly different between tea and control (P > 0.05). Baseline-adjusted net effects on mean 24 h ambulatory blood pressure for systolic and diastolic blood pressure were -0.2 mm Hg (95% CI, -1.5 to 1.0), P = 0.72, and 0.0 mm Hg (95% CI, -1.0 to 0.9), P = 0.95, respectively. Heart rate was significantly lower for tea compared to control during the night-time and early-morning periods (-2.0 (95% CI, -3.2, -0.8) bpm, and -1.9 (95% CI, -3.7, -0.2) bpm, respectively; P < 0.05 for both), but not during the day-time. These results suggest that the longer-term benefits of black tea on blood pressure are unlikely to be due to short-term changes.

The effects of a lupin-enriched diet on oxidative stress and factors influencing vascular function in overweight subjects.

A diet enriched in lupin kernel flour can lower blood pressure, but mechanisms responsible are unclear. Lupin is a source of polyphenols, protein, and L-arginine, factors that may influence blood pressure via effects on oxidative stress and vascular function. Therefore, we aimed to determine the effects of a lupin-enriched diet on oxidative stress and factors influencing vascular function as potential mechanisms for demonstrated benefits on blood pressure. Overweight men and women (n = 88) were recruited to a 16-week parallel-design study. Participants were randomly assigned to replace 15%-20% of their usual daily energy intake with white bread (control) or lupin kernel flour-enriched bread (lupin). All measurements were taken at baseline and 16 weeks. At baseline, plasma F2-isoprostanes and 20-hydroxyeicosatetraenoic acid (20-HETE) were positively associated with blood pressure, and plasma nitrite was negatively associated with blood pressure (p < 0.05). For lupin relative to control, the estimated differences in plasma F2-isoprostanes (45 pmol/L; 95%CI: -68, 158), urinary F2-isoprostanes (17 pmol/mmol creatinine; 95%CI: -43, 76), plasma 20-HETE (75 pmol/L; 95%CI: -91, 241), and plasma nitrite (-0.3 µmol/L; 95%CI: -1.1, 0.4) were not significant. Although regular consumption of lupin-enriched bread can lower blood pressure, these results do not support for the hypothesis that this is via effects on oxidative stress or vascular function.

Predictors of type 2 diabetes and diabetes-related hospitalisation in an Australian Aboriginal cohort.

Predictors of diabetes and diabetes-related hospitalisations were examined in 15-88-year-old Aboriginal Australians (256 women, 258 men), surveyed in 1988-1989. Linkage to death records and hospitalisations to 2002 allowed proportional hazards or negative binomial modelling. Forty-five men (18%) and 59 women (24%) developed diabetes. Risk of diabetes was predicted positively by waist girth (hazard ratio (HR) 1.08, 95% CI 1.04, 1.13), smoking (HR 2.05, 95% CI 1.23, 3.39) and eating processed meats>4 times/month (HR 1.58, 95% CI 1.05, 2.40) and negatively by lower alcohol intake (HR 0.69, 95% CI 0.49, 0.99), preferring wine (HR 0.13, 95% CI 0.02, 0.97) and eating bush meats>4 times/month (HR 0.34, 95% CI 0.13, 0.90). Hospitalisation was predicted positively by smoking (Incidence rate ratio (IRR) 3.72, 95% CI 1.70, 8.18) and eating processed meats (IRR 1.03, 95% CI 1.01, 1.06), and negatively by exercise>or=once/week (IRR 0.23, 95% CI 0.08, 0.65), eating bush meats (IRR 0.95, 95% CI 0.91, 0.99) and trimming fat from meats (IRR 0.53, 95% CI 0.30, 0.94). Length of hospital stay was predicted positively by eating processed meats (HR 1.76, 95% CI 1.23, 2.53) and added salt (HR 1.52, 95% CI 1.02, 2.26) and negatively by lower alcohol intake (HR 0.90, 95% CI 0.40, 0.92) and exercise (HR 0.66, 95% CI 0.46, 0.95). Central obesity and adverse lifestyle increase risk for diabetes or related hospitalisation among Aboriginal Australians.

Acute effects of tea on fasting and non-fasting plasma total homocysteine concentrations in human subjects.

Plasma total homocysteine concentrations (tHcy) are a putative risk factor for CVD. Tea is a rich dietary source of polyphenols and caffeine, both of which may raise tHcy. However, it is possible that much of any effect is transitory and may be influenced by the consumption of food. Our objective was to investigate the acute effect of tea, at a dose representative of ordinary population intakes, on tHcy and to determine whether consumption of a meal influences the magnitude of any effect. Measurements of tHcy were performed in twenty participants at baseline and 3.5 h after drinking three cups of black tea or hot water (consumed at time 0, 1.5 and 3 h) with and without a meal: a total of four treatments administered in random order. Drinking tea resulted in an acute increase in tHcy (0-30 (95 % CI 0.04, 0.56) micromol/l, P=0.022). The meal resulted in an acute decrease in tHcy (-0.42 (95 % CI -0.68, -0.16) micromol/l, P=0.002). There was no interaction between tea and meal on tHcy (P=0.40); that is, the effect of tea on tHcy was not different in the fasting and non-fasting state. Our results suggest that drinking black tea can cause a small acute increase in tHcy and that this effect is not enhanced in the non-fasting state. Given that results of population studies have generally shown a negative association between tea intake and tHcy, the significance of these findings to CVD risk remains uncertain.

Effects of alpha-tocopherol and mixed tocopherol supplementation on markers of oxidative stress and inflammation in type 2 diabetes.

BACKGROUND: Vitamin E isomers may protect against atherosclerosis. The aim of this study was to compare the effects of supplementation with either alpha-tocopherol (alphaT) or mixed tocopherols rich in gamma-tocopherol (gammaT) on markers of oxidative stress and inflammation in patients with type 2 diabetes. METHODS: In a double-blind, placebo-controlled trial, 55 patients with type 2 diabetes were randomly assigned to receive (500 mg/day) (a) alphaT, (b) mixed tocopherols, or (c) placebo for 6 weeks. Cellular tocopherols, plasma and urine F(2)-isoprostanes, erythrocyte antioxidant enzyme activities, plasma inflammatory markers, and ex vivo assessment of eicosanoid synthesis were analyzed pre- and postsupplementation. RESULTS: Neutrophil alphaT and gammaT increased (both P <0.001) with mixed tocopherol supplementation, whereas alphaT (P <0.001) increased and gammaT decreased (P <0.005) after alphaT supplementation. Both alphaT and mixed tocopherol supplementation resulted in reduced plasma F(2)-isoprostanes (P <0.001 and P = 0.001, respectively) but did not affect 24-h urinary F(2)-isoprostanes or erythrocyte antioxidant enzyme activities. Neither alphaT nor mixed tocopherol supplementation affected plasma C-reactive protein, interleukin 6, tumor necrosis factor-alpha, or monocyte chemoattractant protein-1. Stimulated neutrophil leukotriene B(4) production decreased significantly in the mixed tocopherol group (P = 0.02) but not in the alphaT group (P = 0.15). CONCLUSIONS: The ability of tocopherols to reduce systemic oxidative stress suggests potential benefits of vitamin E supplementation in patients with type 2 diabetes. In populations with well-controlled type 2 diabetes, supplementation with either alphaT or mixed tocopherols rich in gammaT is unlikely to confer further benefits in reducing inflammation.

Monocyte-derived macrophages from men and women with Type 2 diabetes mellitus differ in fatty acid composition compared with non-diabetic controls.

We examined whether macrophages from men and women with Type 2 diabetes mellitus (T2DM) exhibited differences in expression of key genes involved in fatty acid metabolism and in fatty acid composition compared with macrophages from non-diabetic controls. Peripheral blood monocytes from subjects with T2DM (n=9) and non-diabetic controls (n=10) were differentiated into macrophages in 10% autologous serum and normal (5mM) or high (22mM) glucose. Levels of PPARalpha, PPARgamma, LXRalpha, SCD and ABCA1 mRNAs were similar in macrophages from subjects with T2DM and controls. At 5mM glucose, macrophage stearic acid (C18:0) was 12.6+/-1.0% of total fatty acids for T2DM compared with 18.1+/-2.0% for controls (p=0.03). Macrophage linoleic acid (C18:2) was 15.5+/-0.8% for T2DM and 9.3+/-2.0% for controls (p=0.005). The ratio of macrophage stearic acid (C18:0)/oleic acid (C18:1) was 0.29 [0.25,0.48] for T2DM versus 0.54 [0.36,0.82] for controls (p=0.04). Compared with non-diabetic controls, macrophages from men and women with T2DM had significantly different fatty acid profiles consistent with increased stearoyl-CoA desaturase (SCD) activity and increased C18:2 accumulation. This pattern of altered macrophage fatty acid composition may be relevant to diabetic atherogenesis.

Lupin-enriched bread increases satiety and reduces energy intake acutely.

BACKGROUND: Protein and fiber may be important determinants of satiety. Lupin kernel flour is a novel food ingredient that is rich in protein and fiber. OBJECTIVE: The objective was to investigate the effects of lupin kernel flour-enriched bread (LB) on satiety and energy intake in humans. DESIGN: Two randomized controlled crossover trials were performed to compare the acute effects of LB with those of white bread (WB). In study 1, the subjects (n = 16) completed 4 treatments 1 wk apart: WB breakfast (as toast) and WB lunch (as sandwiches), WB breakfast and LB lunch, LB breakfast and WB lunch, and LB breakfast and LB lunch. Energy intake at all breakfast meals was matched (1655 kJ), and ad libitum energy intake at lunch, 3 h after breakfast, was measured. In study 2, the subjects (n = 17) completed 2 treatments 1 wk apart: WB breakfast and LB breakfast (each 1655 kJ). Blood samples were taken at baseline and at regular intervals for 3 h after breakfast. RESULTS: In study 1, the LB breakfast resulted in significantly higher self-reported satiety (P < 0.001) and lower energy intake (kJ) at lunch (-488; 95% CI: -798, -178) than did the WB breakfast. The LB lunch resulted in a significantly lower within-meal energy intake (kJ) at lunch (-1028; 95% CI: -1338, -727) than did the WB lunch. In study 2, compared with the WB breakfast, the LB breakfast significantly altered the 3-h postmeal plasma ghrelin response (P = 0.04) and resulted in significantly lower mean 3-h plasma ghrelin concentrations (P = 0.009). CONCLUSION: A novel food enriched in protein and fiber derived from lupin kernel flour significantly influences energy intake acutely.

Differential modulation of cell cycle, apoptosis and PPARgamma2 gene expression by PPARgamma agonists ciglitazone and 9-hydroxyoctadecadienoic acid in monocytic cells.

We sought to compare the effects of the thiazolidinedione ciglitazone with the endogenous fatty acid PPARgamma agonists 9- and 13-hydroxyoctadecadienoic acid (9- and 13-HODE), in U937 monocytic cells. Ciglitazone and 9-HODE inhibited cell proliferation and all three agonists increased cellular content of C18:0 fatty acids. Ciglitazone and 13-HODE resulted in an increased percentage of cells in S phase and ciglitazone reduced the percentage of cells in G2/M phase of cell cycle, whilst 9-HODE increased the percentage of cells in G0/1 and reduced the fraction in S and G2/M phases. 9-HODE selectively induced apoptosis in U937 cells, and increased PPARgamma2 gene expression. Induction of apoptosis by 9-HODE was not abrogated by the presence of the PPARgamma antagonist GW9662. Synthetic (TZD) and endogenous fatty acid ligands for PPARgamma, ciglitazone and 9- and 13-HODE, possess differential, ligand specific actions in monocytic cells to regulate cell cycle progression, apoptosis and PPARgamma2 gene expression.

Drinking tea is associated with lower plasma total homocysteine in older women.

Dietary polyphenols are suggested to elevate plasma total homocysteine concentration (tHcy). Although tea is rich in polyphenols, it has been associated with lower tHcy, which may be due to its folate content. Our aims were to investigate relationships of tea intake and 4-O-methylgallic acid (4OMGA)--a biomarker of exposure to tea-derived polyphenols--with tHcy in older women. In a cross-sectional study of 232 women over 70 years of age, we measured tHcy, tea intake, 24 h urinary excretion of 4OMGA, and red cell folate. Tea intake and 4OMGA excretion were inversely related to tHcy. Tea intake (>2 cups) and 4OMGA excretion above the median were associated with lower tHcy by approximately 1 mmol/L (P <0.01). Red cell folate was not associated with tea intake or 4OMGA excretion. The observed lower tHcy in women with higher tea intake is consistent in direction and magnitude with previous epidemiological studies, but any mechanisms remain unclear.

Effect of alcohol on cytochrome p450 arachidonic acid metabolism and blood pressure in rats and its modulation by red wine polyphenolics.

Alcohol-induced hypertension is well recognized with clear evidence for a direct pressor effect of chronic alcohol consumption provided by a number of intervention studies in humans. In experimental animals, the effect of alcohol on blood pressure is less consistent; however, in Sprague-Dawley rats, alcohol feeding consistently induces a hypertensive response. The mechanism of alcohol-induced hypertension is not clearly understood. Ethanol is known to induce certain cytochrome P450 (CYP) enzymes, particularly the 2E1 isoform, which has been shown to metabolise arachidonic acid (AA) to the 19-hydroxy metabolite (19-HETE), which could have pro-hypertensive activity; CYP4A, by comparison, is the principal AA omega-hydroxylase in the liver. Polyphenolic compounds, such as flavonoids, have been shown to inhibit some CYPs. 2. In this study, we determined the effect of alcohol administration on blood pressure and CYP-dependent AA metabolism in the rat and its possible modulation by red wine polyphenols. 3. Thirty male Sprague-Dawley rats were randomly allocated to three groups, which received water, low-dose ethanol (5% v/v) or red wine (diluted to contain 5% ethanol) for a period of 9 weeks. Bodyweight and blood pressure were measured weekly and 24h urine collected at baseline and every 2 weeks. Animals were killed at 9 weeks and blood and tissue samples were collected. The blood pressure of rats fed with alcohol increased significantly over the period of the study compared with controls (P<0.001). The blood pressure of animals fed 5% alcohol in the form of red wine was not significantly different from controls over the study period. The urinary excretion of 20-HETE did not differ significantly among the treatment groups over the study period and there was no effect of any treatment on the metabolism of AA by renal microsomes. Red wine, but not administration of the relatively low dose of alcohol alone, increased the expression of CYP2E1 protein in the liver and kidney and CYP4A in the kidney. Both red wine and alcohol decreased CYP4A protein levels in the liver compared with controls. 4. Our results suggest that constituents of red wine, possibly polyphenols, can attenuate the alcohol-induced rise in blood pressure in the Sprague-Dawley rat, although this effect does not appear to be mediated by the inhibition of CYP-derived AA metabolism.

Nitration of gamma-tocopherol prevents its oxidative metabolism by HepG2 cells.

Gamma-tocopherol (gammaT) is one of the major forms of vitamin E consumed in the diet. Previous reports have suggested increased levels of nitrated gamma-tocopherol (5-NO2-gammaT) in smokers and individuals with conditions associated with elevated nitrative stress. The monitoring of 5-NO2-gammaT and its possible metabolite(s) may be a useful marker of reactive nitrogen species generation in vivo. The major pathway for the metabolism of gammaT is the cytochrome P450 dependent oxidation to its water-soluble metabolite gamma-CEHC, which is excreted in urine. In order to determine if 5-NO2-gammaT could be metabolised via the same route and detected in urine we developed a sensitive gas chromatography-mass spectrometry assay for 5-NO2-gamma-CEHC. 5-NO2-gamma-CEHC was synthesised and its structure confirmed by proton nuclear magnetic resonance and mass spectrometry. While gamma-CEHC was abundant in urine from healthy volunteers, as well as patients with coronary heart disease and type 2 diabetes, 5-NO2-gamma-CEHC was undetectable (limit of detection of 5 nM). To understand this observation we examined the uptake and metabolism of gammaT and 5-NO2-gammaT by HepG2 cells. gammaT was readily incorporated into cells and metabolised to gamma-CEHC over a period of 48 hours. In contrast, 5-NO2-gammaT was poorly incorporated into HepG2 cells and not metabolised to 5-NO2-gamma-CEHC over the same time period. We conclude that nitration of gammaT prevents its incorporation into liver cells and therefore its metabolism to the water-soluble metabolite. Whether 5-NO2-gammaT could be metabolised via other pathways in vivo requires further investigation.

Red wine and beer elevate blood pressure in normotensive men.

A positive relationship between alcohol consumption and blood pressure (BP) is well-established but the relative effect of specific alcoholic beverages is controversial. This study aimed to determine whether red wine may improve vascular function and have less of an impact on blood pressure because of its high content of antioxidant vasodilator polyphenolic compounds. Healthy normotensive men entered a 4-period crossover study comparing in random order 4 weeks of control-abstinence with similar periods of daily consumption of red wine (375 mL; 39 grams alcohol), de-alcoholized red wine (375 mL), or beer (1125 mL; 41 grams alcohol). Ambulatory systolic BP and diastolic BP and heart rate (HR) were measured together with vascular function as assessed by flow-mediated dilatation (FMD) and glyceryl trinitrate-mediated (GTNMD) dilatation of the brachial artery. The systolic and diastolic BP and HR were not different between control-abstinence and de-alcoholized red wine. However, compared with control-abstinence, both red wine and beer increased awake systolic BP (2.9 and 1.9 mm Hg, respectively; P<0.05) and asleep HR (5.0 and 4.4 bpm; P<0.05). There were no specific effects of red wine, de-alcoholized red wine, or beer on FMD or GTNMD. Daily consumption of approximately 40 grams alcohol as either red wine or beer for 4 weeks results in similar increases in systolic BP and HR. De-alcoholized red wine did not lower BP, and neither red wine nor de-alcoholized red wine influenced vascular function, suggesting that red wine polyphenolics do not have a significant role in mitigating the blood pressure-elevating effects of alcohol in men.

Acute effects of tea on fasting and postprandial vascular function and blood pressure in humans.

BACKGROUND: Effects of regular exposure to polyphenolic compounds found in tea, leading to improved endothelial function and blood pressure, may reduce cardiovascular disease risk. Controlled trials in humans have found that ingestion of tea can improve endothelial function, but also cause a rapid onset acute increase in blood pressure. OBJECTIVE: To examine the acute effects of tea consumption on fasting and postprandial vascular function and blood pressure. METHODS: Endothelium-dependent dilatation of the brachial artery, assessed using ultrasound and blood pressure were measured in 20 participants with a history of coronary artery disease. Measurements were performed at baseline and at 3.5 h (blood pressure) and 4 h (endothelial function) after drinking three cups of black tea or hot water (consumed at time = 0, 1.5 and 3 h) with and without a high-fat (50 g) meal: a total of four treatments administered in random order. RESULTS: The high-fat meal did not impair endothelial function. In comparison to water alone, endothelium-dependent dilatation was increased by the meal with tea (1.7 (0.4, 3.0)%, P = 0.02), but was not significantly altered by the tea alone (0.7 (-0.6, 2.0)%, P = 0.32). Systolic blood pressure was significantly increased by tea alone in comparison to each of the other three groups: water alone (9.3 (4.5, 14.1) mmHg, P = 0.0003), meal with water (9.8 (5.0, 14.6) mmHg, P = 0.0001) and meal with tea (7.2 (2.4,12.0) mmHg, P = 0.004). Consumption of a meal negated the acute increase in systolic blood pressure found with tea in the fasting state. CONCLUSION: Consumption of food may alter the acute effects of tea on vascular function and blood pressure.

The combination of vitamin C and grape-seed polyphenols increases blood pressure: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: There is growing evidence that oxidative stress contributes to the pathogenesis of hypertension and endothelial dysfunction. Thus, dietary antioxidants may beneficially influence blood pressure (BP) and endothelial function by reducing oxidative stress. OBJECTIVE: To determine if vitamin C and polyphenols, alone or in combination, can lower BP, improve endothelial function and reduce oxidative stress in hypertensive individuals. DESIGN: A total of 69 treated hypertensive individuals with a mean 24-h ambulatory systolic blood pressure > or = 125 mmHg participated in a randomized, double-blind, placebo-controlled, factorial trial. Following a 3-week washout, participants received 500 mg/day vitamin C, 1000 mg/day grape-seed polyphenols, both vitamin C and polyphenols, or neither for 6 weeks. At baseline and post-intervention, 24-h ambulatory BP, ultrasound-assessed endothelium-dependent and -independent vasodilation of the brachial artery, and markers of oxidative damage, (plasma and urinary F2-isoprostanes, oxidized low-density lipoproteins and plasma tocopherols), were measured. RESULTS: A significant interaction between grape-seed and vitamin C treatments for effects on BP was observed. Vitamin C alone reduced systolic BP versus placebo (-1.8 +/- 0.8 mmHg, P = 0.03), while polyphenols did not (-1.3 +/- 0.8 mmHg, P = 0.12). However, treatment with the combination of vitamin C and polyphenols increased systolic BP (4.8 +/- 0.9 mmHg versus placebo; 6.6 +/- 0.8 mmHg versus vitamin C; 6.1 +/- 0.9 mmHg versus polyphenols mmHg, each P < 0.0001) and diastolic BP (2.7 +/- 0.6 mmHg, P < 0.0001 versus placebo; 1.5 +/- 0.6 mmHg, P = 0.016 versus vitamin C; 3.2 +/- 0.7 mmHg, P < 0.0001 versus polyphenols). Endothelium-dependent and -independent vasodilation, and markers of oxidative damage were not significantly altered. CONCLUSION: Although the mechanism remains to be elucidated, these results suggest caution for hypertensive subjects taking supplements containing combinations of vitamin C and polyphenols.